α,β-Dihydropolyprenyl derivatives for treating hepatitis

ABSTRACT

An α,β-dihydropolyprenyl derivative having the formula (I): ##STR1## wherein X represents a group of --COOR 1  or --CH 2  OR 2  in which R 1  is the hydrogen atom or an alkyl group having one to four carbon atoms and R 2  is the hydrogen atom or an aliphatic acyl group having one to four carbon atoms; and n is an integer of one to four. A process for the preparation of the α,β-dihydropolyprenyl derivative and a therapeutic agent for treatment of liver diseases comprising the same are also disclosed.

This is a division of application Ser. No. 269,930, filed May 28, 1981, now U.S. Pat. No. 4,481,217, issued Nov. 6, 1984.

This invention relates to α,β-dihydropolyprenyl derivatives having the formula (I): ##STR2## wherein X represents a --COOR₁ group or a --CH₂ OR₂ group, in which R₁ is hydrogen or a lower alkyl group and R₂ is hydrogen or an aliphatic acyl group having one to four carbon atoms; and n is an integer of one to four. The invention further relates to processes for the preparation of compounds of formula (I) and therapeutic compositions for treatment of liver diseases comprising compounds of formula (I).

More particularly, this invention relates to α,β-dihydropolyprenylcarboxylic acids and derivatives thereof having the formula (I) in which X represents --COOR₁ group, that is, compounds having the following formula (II): ##STR3## in which R₁ and n have the same meanings as set forth above, and further relates to α,β-dihydropolyprenyl alcohols and derivatives thereof having the formula (I) in which X represents a --CH₂ OR₂ group, that is, compounds having the following formula (III): ##STR4## in which R₂ and n have the same meanings as set forth above.

In the above-mentioned formulae, R₁ can be an alkyl having 1 to 6, preferably 1 to 4, carbon atoms, such as methyl, ethyl, i-propyl, n-propyl, t-butyl, n-butyl, n-pentyl and n-hexyl and R₂ can be acetyl, propionyl, butyryl or isobutyryl.

The α,β-dihydropolyprenylcarboxylic acids and derivatives thereof having the formula (II) can be prepared by the following reaction steps:

(a) a compound having the formula (VII): ##STR5## in which n is a integer of one to four, and a compound having the formula (VIII):

    CN--CH.sub.2 --COOR.sub.5                                  (VIII)

in which R₅ represents a lower alkyl group are reacted to obtain a compound having the formula (IX): ##STR6## in which n and R₅ have the same meanings as set forth above;

(b) the compound of the formula (IX) is then

reduced to obtain a compound having the formula (X): ##STR7## in which n and R₅ have the same meanings as set forth above; (c) the compound of the formula (X) is subjected to a decarboxylation reaction in the presence of a base to obtain a compound having the formula (IV): ##STR8## in which n has the same meaning as set forth above;

(d) the compound of the formula (IV) is hydrolyzed in the presence of a base to obtain a compound having the formula (II-1): ##STR9## in which n has the same meaning as set forth above;

and if a derivative of the compound of formula (II-1) is desired,

(e) the compound of the formula (II-1) or a reactive derivative thereof is reacted with a compound having the formula (V):

    R.sub.3 --OH                                               (V)

in which R₃ represents an alkyl group having one to four carbon atoms, to obtain a compound having the formula (II-2): ##STR10## in which n and R₃ have the same meanings as set forth above.

The reaction between the compound of the formula (VII) and the compound of the formula (VIII) in the (a) step can be carried out in the presence of a base or an acid, such as ammonium acetate--acetic acid, piperidine or morpholine.

The reduction reaction in the (b) step can be carried out using a reducing agent such as sodium borohydride.

Examples of the bases to be employed in the (c) and (d) steps include potassium hydroxide, sodium hydroxide and pyridine--copper.

The reaction in the (e) step can be carried out by a conventional esterification method. For instance, the carboxylic acid of the formula (II-1) can be converted into its ester form by the reaction in the presence of a condensing agent, such as p-toluenesulfonyl chloride, dicyclohexylcarbodiimide, ethyl polyphosphate, ethyl chlorocarbonate, oxalyl chloride or trifluoroacetic acid. The reaction in the (e) step can be carried out using a reactive derivative of the carboxylic acid of the formula (II-1). Examples of the reactive derivatives include the corresponding acid chloride and the corresponding acid anhydride.

The α,β-dihydropolyprenyl alcohol and derivatives thereof having the formula (III) can be prepared by the following reaction steps:

(f) the compound having the above-mentioned formula (II-1) is reduced in the presence of a reducing agent to obtain a compound having the formula (III-1): ##STR11## in which n is an integer of one to four;

and if a derivative of the compound of formula (III-1) is desired,

(g) the compound of the formula (III-1) is reacted with a compound having the formula (VI):

    R.sub.4 --OH                                               (VI)

in which R₄ represents an aliphatic acyl group having one to four carbon atoms or a reactive derivative thereof, to obtain a compound having the formula (III-2): ##STR12## in which n and R₄ have the same meanings as set forth above.

The reduction reaction in the (f) step can be carried out in an ether solvent, such as diethyl ether or tetrahydrofuran, and in the presence of a reducing agent, such as lithium aluminum hydride.

The reaction in the (g) step can be carried out by a conventional esterification method. For instance, the compound of the formula (III-1) can be subjected to esterification in the form of its reactive derivative, such as the corresponding acid chloride or the corresponding acid anhydride. If the compound of the formula (III-1) is employed per se for the esterification reaction, the reaction can be carried out in the presence of a condensing agent, such as p-toluenesulfonyl chloride, dicyclohexylcarbodiimide, ethyl polyphosphate, ethyl chlorocarbonate, oxalyl chloride or trifluoroacetic acid.

The α,β-dihydropolyprenyl derivatives of the formula (I) according to this invention are of value as a therapeutic agent for the treatment of liver diseases. The liver possibly suffers from various diseases, such as inflammation, degeneration, necrosis, failure of the function for secretion of biliary products and abnormal carbohydrate metabolism, due to a variety of causes, such as excessive drinking or alcoholic drinks, malnutrition, viruses, chemical substances and toxic materials. The α,β-dihydropolyprenyl derivatives of the formula (I) are effective for treating these liver diseases or for preventing these liver diseases.

The α,β-dihydropolyprenyl derivatives of the formula (I), according to the invention, can be administered orally or parenterally to human beings. Oral administration is particularly preferred. The dosage generaly ranges from 50 to 2,000 mg per day for an adult, and more preferably, a dosage ranging from 200 to 600 mg./day for an adult human being is employed. The compound of the formula (I) can be administered in a variety of forms, such as granules, powders, hard capsules, tablets and soft capsules. These forms are conventionally employed in pharmaceutical preparations and they can be prepared in the conventional manners.

The present invention will be further described by reference to the following examples relating to pharmacological activity and preparation of compounds. However, these examples do not restrict the scope of the invention.

PHARMACOLOGICAL TESTS Compounds for testing

(A) (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid

(B) ethyl (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate

(C) (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrien-1-ol

(D) (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienyl acetate

Test method

Activity against liver disease (hepatitis) induced by D-galactosamine

D-Galactosamine hydrochloride and the above-listed compound were administered (1) subcutaneously in the dosage of 200 mg./kg. each time and (2) orally in the dosage of 400 mg./kg. each time, respectively, to rats (SD strain, weight: approximately 250 g.) according to the schedule described hereinafter. After completion of the administrations, the blood was collected from the rats and there were measured the GOT value, GPT value and alkali phosphotase value, all of which are indicative of the degree of liver disease.

Each test compound was administered in the form of a suspension thereof in a 5% aqueous gum arabic solution. The D-galactosamine hydrochloride was administered in the form of an aqueous solution thereof in distilled water adjusted to pH 7 by addition of potassium hydroxide.

There were provided the test compound groups (nine rats per each group) in which the rats were administered with the test compound and with D-galactosamine hydrochloride; a control group (fourteen rats) in which the rats were administered with a plain 5% aqueous gum arabic solution free of the test compound and with D-galactosamine hydrochloride; and a normal group (eight rats) in which the rats were not administered with either the test compound or D-galactosamine hydrochloride.

Administration schedule

    ______________________________________                                         Hour         Adminstration                                                     ______________________________________                                         0      (start)   test compound                                                 4                test compound and D-galactosamine                                              hydrochloride                                                 10               test compound and D-galactosamine                                              hydrochloride                                                 24               test compound and D-galactosamine                                              hydrochloride                                                 28               blood collection                                              ______________________________________                                    

Test results

The results are set forth in Table 1.

                  TABLE 1                                                          ______________________________________                                                    Subject for testing                                                              GPT value  GOT value Alkali phos-                                 Test         (carmen    (carmen   photase value                                group        unit)      unit)     (KA - u)                                     ______________________________________                                         Normal group  34.8 ± 129.4 ±                                                                               49.3 ±                                                  1.9        12.6      4.4                                         Control group                                                                               395.7 ± 573.7 ±                                                                               67.4 ±                                                  49.3       59.1      2.9                                         Test compound group                                                            Compound A   208.3 ± 312.4 ±                                                                               56.2 ±                                                  30.7       39.5      4.1                                         Compound B   199.7 ± 307.1 ±                                                                               55.8 ±                                                  28.9       40.1      3.8                                         Compound C   185.6 ± 337.7 ±                                                                               54.2 ±                                                  41.4       45.1      6.1                                         Compound D   178.7 ± 315.3 ±                                                                               53.5 ±                                                  46.9       50.6      5.8                                         ______________________________________                                    

Toxicity

Each of the above-listed compounds, A, B, C and D was suspended in a 5% aqueous gum arabic solution and then was administered orally to ten rats (Wistar strain) in the dosage of 4,000 mg./kg. No deaths of the rats were observed.

EXAMPLE 1 (E, E)-3,7,11,15-Tetramethyl-6,10,14-hexadecatrienoic acid (a) Ethyl (E, E)-2-cyano-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate

In 200 ml. of benzene was dissolved 50 g. of farnesyl acetone, and then 28 g. of ethyl cyanoacetate, 5 g. of ammonium acetate and 5 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours with removal of the produced water. The reaction mixture then was washed with water and dried. To this mixture there was added dropwise a solution of 4.3 g. of sodium borohydride in 50 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 50 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography to obtain 50.5 g. of the desired oily product.

(b) (E, E)-3,7,11,15-Tetramethyl-6,10,14-hexadecatrienonitrile

To the entirety of the product obtained in the above (a) step, there were added 29 g. of sodium hydroxide and 100 ml. of propylene glycol, and the mixture was stirred at room temperature for 10 min. The reaction mixture was made acidic by addition of 6N hydrochloric acid, and was then extracted with benzene. The extract was then washed with water and dried. The solvent was then removed by evaporation. The obtained oily product was dissolved in 100 ml. of pyrydine, and the resulting solution was refluxed for 2 hours after addition of 0.5 g. of copper powder. Subsequently, the copper powder was removed by filtration and the solvent was removed by evaporation. The residue was dissolved in n-hexane, washed with water and dried. The solvent was then removed by evaporation and the residue was purified by silica gel column chromatography to obtain 34 g. of the desired oily product.

(c) (E, E)-3,7,11,15-Tetramethyl-6,10,14-hexadecatrienoic acid

To 34 g. of the product obtained in the above (b) step, there were added 23 g. of potassium hydroxide, 10 ml. of water and 70 ml. of propylene glycol, and the mixture was stirred at 130° C. for 7 hours. The reaction mixture was made acidic by addition of hydrochloric acid, and was then extracted with n-hexane. The extract was washed with water and dried, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography to obtain 30 g. of the desired oily product.

Infrared Absorption Spectrum (cm⁻¹, neat): 3,600-2,400, 1,710.

Mass Spectrum: 306 (M⁺).

Elementary Analysis (calculated for C₂₀ H₃₄ O₂):

    ______________________________________                                                         C    H                                                         ______________________________________                                         Calculated (%)    78.38  11.18                                                 Found (%)         78.21  11.02                                                 ______________________________________                                    

NMR Spectrum (δ, CDCl₃): 0.99 (3H, s), 1.2-1.5 (3H, m), 1.6 (9H, s), 1.72 (3H, s), 1.9-2.2 (10H, m), 2.20 (2H, d), 5.0-5.2 (3H, m), 11.3 (1H, br).

EXAMPLE 2 Ethyl (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate

In 50 ml. of anhydrous tetrahydrofuran was dissolved 9.2 g. of the product obtained in the (c) step of Example 1. To the resulting solution were added successively 3 g. of triethylamine and 3.3 g. of ethyl chlorocarbonate at 0° C., and the mixture was then stirred for 20 min. The reaction mixture was, after addition of 50 ml. of ethanol, refluxed for 2 hours, and the solvent was then removed by evaporation. The residue was extracted with 100 ml of n-hexane, and the extract was washed with water and dried. The solvent was removed by evaporation, and the residual oil was purified by silica gel column chromatography to obtain 8 g. of the desired oily product.

Infrared Absorption Spectrum (cm⁻¹, neat): 1,735, 1,300, 1,050.

Mass Spectrum: 334 (M⁺).

Elementary Analysis (calculated for C₂₂ H₃₈ O₂):

    ______________________________________                                                         C    H                                                         ______________________________________                                         Calculated (%)    78.98  11.45                                                 Found (%)         79.10  11.58                                                 ______________________________________                                    

NMR spectrum (δ, CDCl₃): 0.99 (3H, s), 1.2-1.5 (3H, m), 1.3 (3H, t), 1.6 (9H, s), 1.72 (3H, s), 1.9-2.2 (10H, m), 2.20 (2H, d), 4.2 (2H, q), 5.0-5.2 (3H, m).

EXAMPLE 3 (E)-3,7,11-Trimethyl-6,10-dodecadienoic acid (a) Ethyl (E)-2-cyano-3,7,11-trimethyl-6,10-dodecadienoate

In 200 ml. of benzene was dissolved 50 g. of geranyl acetone, and then 42 g. of ethyl cyanoacetate, 6 g. of ammonium acetate and 6 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours while removing the produced water. The reaction mixture was washed with water and dried. To this was added dropwise a solution of 5.7 g. of sodium borohydride in 40 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 60 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was then removed by evaporation and the residue was purified by silica gel column chromatography to obtain 59 g. of the desired oily product.

(b) (E)-3,7,11-Trimethyl-6,10-dodecadienonitrile

To the entirety of the product obtained in the above (a) step, there were added 39 g. of sodium hydroxide and 120 ml. of propylene glycol, and the mixture was stirred at room temperature for 10 min. The reaction mixture was then made acidic by addition of 6N hydrochloric acid, and was then extracted with benzene. The extract was then washed with water and dried. The solvent was then removed by evaporation. The residue was dissolved in 120 ml. of pyridine, and the resulting solution was refluxed for 2 hours after addition of 0.6 g. of copper powder. Subsequently, the copper powder was removed by filtration and the solvent was removed by evaporation. The residue was dissolved in n-hexane, washed with water and dried. The solvent was then removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 45 g. of the desired oily product.

(c) (E)-3,7,11-Trimethyl-6,10-dodecadienoic acid

To 40 g. of the product obtained in the above (b) step, there were added 35 g. of potassium hydroxide, 15 ml. of water and 80 ml. of propylene glycol, and the mixture was stirred at 130° C. for 7 hours. The reaction mixture was then made acidic by addition of hydrochloric acid, and was then extracted with n-hexane. The extract was washed with water and dried, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography to obtain 36 g. of the desired oily product.

Infrared Absorption Spectrum (cm⁻¹, neat): 3,600-2,400, 1,710.

Mass Spectrum: 238 (M⁺).

Elementary Analysis (calculated for C₁₅ H₂₆ O₂):

    ______________________________________                                                         C    H                                                         ______________________________________                                         Calculated (%)    75.58  11.00                                                 Found (%)         75.44  10.91                                                 ______________________________________                                    

NMR Spectrum (δ, CDCl₃): 0.99 (3H, s), 1.2-1.5 (3H, m), 1.6 (6H, s), 1.72 (3H, s), 1.9-2.2 (6H, m), 2.20 (2H, d), 5.0-5.2 (2H, m), 11.3 L (1H, br).

EXAMPLES 4-16

In Examples 4 through 16, a variety of compounds according to the invention were prepared in the same manner as described in Examples 1 through 3. The compounds and the resulting data are set forth in Table 2.

                                      TABLE 2                                      __________________________________________________________________________      ##STR13##                                                  (II)                                    Analysis:                                                                Molecular Formula                                                                     ##STR14##                                                                              Mass Spectrum                                                                        NMR Spectrum                               Ex  n  R.sub.1 Property                                                                             C    H   (M.sup.+)                                                                           (δ, CDCl.sub.3)                       __________________________________________________________________________     4   1  H       C.sub.10 H.sub.18 O.sub.2 Oil                                                         ##STR15##                                                                           ##STR16##                                                                         170  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.6 (3H, s), 1.72 (3H,                                                         s), 1.9˜2.2 (2H, m), 2.20 (2H,                                           d), 5.0˜5.2 (1H, m), 11.3 (1H,                                           br)                                         5   1  CH.sub.3                                                                               C.sub.11 H.sub.20 O.sub.2 Oil                                                         ##STR17##                                                                           ##STR18##                                                                         184  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.6 (3H, s), 1.72 (3H,                                                         s), 1.9˜2.2 (2H, m), 2.20 (2H,                                           d), 3.7 (3H, s), 5.0˜5.2 (1H,                                            m)                                          6   1  CH.sub.2 CH.sub.3                                                                      C.sub.12 H.sub.22 0.sub.2 Oil                                                         ##STR19##                                                                           ##STR20##                                                                         198  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.3 (3H, t), 1.6 (3H, s), 1.72 (3H,                                            s), 1.9˜2.2 (2H, m), 2.20 (2H,                                           d), 4.2 (2H, q), 5.0˜5.2 (1H,                                            m)                                          7   1  CH.sub.2 CH.sub.2 CH.sub.3                                                             C.sub.13 H.sub.24 O.sub.2 Oil                                                         ##STR21##                                                                           ##STR22##                                                                         212  0.99 (3H, s), 1.0˜1.3 (5H, m),                                           1.2˜1.5 (3H, m), 1.6 (3H, s),                                            1.72 (3H, s), 1.9˜2.2 (2H, m),                                           2.20 (2H, d), 4.2 (2H,                                                         q), 5.0˜5.2 (1H, m)                   8   2  CH.sub.3                                                                               C.sub.16 H.sub.28 O.sub.2 Oil                                                         ##STR23##                                                                           ##STR24##                                                                         252  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.6 (6H, s), 1.72 (3H,                                                         s), 1.9˜2.2 (6H, m), 2.20 (2H,                                           d), 3.7 (3H, s), 5.0˜5.2 (2H,                                            m)                                          9   2  CH.sub.2 CH.sub.3                                                                      C.sub.17 H.sub.30 O.sub.2 Oil                                                         ##STR25##                                                                           ##STR26##                                                                         266  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.3 (3H, t), 1.6 (6H, s), 1.72 (3H,                                            s), 1.9˜2.2 (6H, m), 2.20 (2H,                                           d), 4.2 (2H, q), 5.0˜5.2 (2H,                                            m)                                          10  2  CH.sub.2 CH.sub.2 CH.sub.3                                                             C.sub.18 H.sub.32 O.sub.2 Oil                                                         ##STR27##                                                                           ##STR28##                                                                         280  0.99 (3H, s), 1.0˜1.3 (5H, m),                                           1.2˜1.5 (3H, m), 1.6 (6H, s),                                            1.72 (3H, s), 1.9˜2.2 (6H, m),                                           2.20 (2H, d), 4.2 (2H,                                                         q), 5.0˜5.2 (2H, m)                   11  3  CH.sub.3                                                                               C.sub.21 H.sub.36 O.sub.2 Oil                                                         ##STR29##                                                                           ##STR30##                                                                         320  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.6 (9H, s), 1.72 (3H,                                                         s), 1.9˜2.2 (10H, m), 2.20 (2H,                                          d), 3.7 (3H, s), 5.0˜5.2 (3H,                                            m)                                          12  3  CH.sub.2 CH.sub.2 CH.sub.3                                                             C.sub.23 H.sub.40 O.sub.2 Oil                                                         ##STR31##                                                                           ##STR32##                                                                         348  0.99 (3H, s), 1.0˜1.3 (5H, m),                                           1.2˜1.5 (3H, m), 1.6 (9H, s),                                            1.72 (3H, s), 1.9˜2.2 (10H, m),                                          2.20 (2H, d), 4.2 (2H,                                                         q), 5.0˜5.2 (3H, m)                   13  4  H       C.sub.25 H.sub.42 O.sub.2 Oil                                                         ##STR33##                                                                           ##STR34##                                                                         374  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.6 (12H, s), 1.72 (3H,                                                        s), 1.9˜2.2 (14H, m), 2.20 (2H,                                          d), 5.0˜5.2 (1H, m), 11.3 (1H,                                           br)                                         14  4  CH.sub.3                                                                               C.sub.26 H.sub.44 O.sub.2 Oil                                                         ##STR35##                                                                           ##STR36##                                                                         388  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.6 (12H, s), 1.72 (3H,                                                        s), 1.9˜2.2 (14H, m), 2.20 (2H,                                          d), 3.7 (3H, s), 5.0˜5.2 (4H,                                            m)                                          15  4  CH.sub.2 CH.sub.3                                                                      C.sub.27 H.sub.46 O.sub.2 Oil                                                         ##STR37##                                                                           ##STR38##                                                                         402  0.99 (3H, s), 1.2˜1.5 (3H, m),                                           1.3 (3H, q), 1.6 (12H, s), 1.72 (3H,                                           s), 1.9˜2.2 (14H, m), 2.20 (2H,                                          d), 4.2 (2H, q), 5.0˜5.2 (4H,                                            m)                                          16  4  CH.sub.2 CH.sub.2 CH.sub.3                                                             C.sub.28 H.sub.48 O.sub.2 Oil                                                         ##STR39##                                                                           ##STR40##                                                                         416  0.99 (3H, s), 1.0˜1.3 (5H, m),                                           1.2˜1.5 (3H, m), 1.6 (12H, s),                                           1.72 (3H, s), 1.9˜2.2 (14H, m),                                          2.20 (2H, d), 4.2 (2H, q),                                                     5.0˜5.2 (4H, m)                       __________________________________________________________________________

EXAMPLE 17 (E, E)-3,7,11,15-Tetramethyl-6,10,14-hexadecatrien-1-ol

To 150 ml. of anhydrous diethyl ether there was added 1.9 g. of lithium aluminum hydride. To the mixture was dropwise added, under stirring and at 10° C., 1.53 g. of the carboxylic acid compound obtained in Example 1. The resulting mixture was then stirred at room temperature for 1 hour, and 1 ml. of ethyl acetate and 1 ml. of water were then added thereto. The mixture was subsequently washed with water and dried. The solvent was removed by evaporation and the resulting residual oil was purified by silica gel column chromatography to obtain 13.8 g. of the desired oily product.

Infrared Absorption Spectrum (cm⁻¹, neat): 3,640.

Mass Spectrum: 292 (M⁺).

Elementary Analysis (calculated for C₂₀ H₃₆ O):

    ______________________________________                                                         C    H                                                         ______________________________________                                         Calculated (%)    82.12  12.40                                                 Found (%)         82.03  12.31                                                 ______________________________________                                    

NMR Spectrum (δ, CDCl₃): 0.99 (3H, d), 1.2-1.5 (5H, m), 1.6 (9H, s), 1.72 (3H, s), 1.9-2.2 (11H, m), 3.6 (2H, t), 5.0-5.2 (3H, m).

EXAMPLE 18 (E, E)-3,7,11,15-Tetramethyl-6,10,14-hexadecatrienyl acetate

In 10 ml. of pyridine was dissolved 2.9 g. of the product obtained in Example 17, and to the solution was added 1.1 g. of acetic anhydride under stirring. The resulting mixture was then refluxed for 1 hour. The reaction mixture was then poured into 50 ml. of water, and was then extracted with n-hexane. The extract was washed with water and dried. The solvent was removed by evaporation. The residual oily product was purified by silica gel column chromatography to obtain 3.1 g. of the desired oily product.

Infrared Absorption Spectrum (cm⁻¹, neat): 1,735, 1,300, 1,050.

Mass Spectrum: 334 (M⁺).

Elementary Analysis (calculated for C₂₂ H₂₈ O₂):

    ______________________________________                                                         C    H                                                         ______________________________________                                         Calculated (%)    78.98  11.45                                                 Found (%)         78.82  11.41                                                 ______________________________________                                    

NMR Spectrum (δ, CDCl₃): 0.99 (3H, d), 1.2-1.5 (5H, m), 1.6 (9H, s), 1.72 (3H, s), 1.9-2.2 (11H, m), 2.0 (3H, s), 4.2 (2H, t), 5.0-5.2 (3H, m).

EXAMPLE 19 (E)-3,7,11-Trimethyl-6,10-dodecadien-1-ol

To 150 ml. of anhydrous diethyl ether there was added 1.9 g. of lithium aluminum hydride. To the mixture was dropwise added, under stirring and at 10° C., 11.9 g. of the carboxylic acid compound obtained in Example 3. The resulting mixture was then stirred at room temperature for 1 hour, and then 1 ml. of ethyl acetate and 1 ml. of water were added thereto. The mixture was subsequently washed with water and dried. The solvent was removed by evaporation and the resulting residual oil was purified by silica gel column chromatography to obtain 10.3 g. of the desired oily product.

Infrared Absorption Spectrum (cm⁻¹, neat): 3,640.

Mass Spectrum: 224 (M⁺).

Elementary Analysis (calculated for C₁₅ H₂₈ O):

    ______________________________________                                                         C    H                                                         ______________________________________                                         Calculated (%)    80.29  12.58                                                 Found (%)         80.14  12.51                                                 ______________________________________                                    

NMR Spectrum (δ, CDCl₃): 0.99 (3H, d), 1.2-1.5 (5H, m), 1.6 (6H, s), 1.72 (3H, s), 1.9-2.2 (7H, m), 3.6 (2H, d), 5.0-5.2 (2H, m).

EXAMPLES 20-32

In Examples 20 through 32, a variety of compounds according to the invention were prepared in the same manner as described in Examples 17 through 19. The compounds and the resulting data are set forth in Table 3.

                                      TABLE 3                                      __________________________________________________________________________      ##STR41##                                   (III)                                                Analysis:                                                                Molecular Formula                                                                     ##STR42##                                                                               Mass Spectrum                                                                        NMR Spectrum                                Ex.                                                                               n R.sub.1 Property                                                                             C    H    (M.sup.+)                                                                           (δ, CDCl.sub.3)                        __________________________________________________________________________     20 1 H       C.sub.10 H.sub.20 O Oil                                                               ##STR43##                                                                           ##STR44##                                                                          156  0.99 (3H, d), 1.2˜1.5 (5H, m),                                           1.6 (3H, s), 1.72 (3H, s),                                                     1.9˜2.2 (3H, m), 3.6 (2H, t),                                            5.0˜5.2 (1H, m)                        21 1 CH.sub.3 CO                                                                            C.sub.12 H.sub.22 O.sub.2 Oil                                                         ##STR45##                                                                           ##STR46##                                                                          198  0.99 (3H, d), 1.2˜1.5 (5H, m),                                           1.6 (3H, s), 1.72 (3H, s),                                                     1.9˜2.2 (2H, m), 2.0 (3H, s), 4.2                                        (2H, t), 5.0˜ 5.2 (1H, m)              22 1 CH.sub.3 CH.sub.2 CO                                                                   C.sub.13 H.sub.24 O.sub.2 Oil                                                         ##STR47##                                                                           ##STR48##                                                                          212  0.99 (3H, d), 1.1 (3H,                                                         t), 1.2˜1.5 (5H, m), 1.6 (3H, s),                                        1.72 (3H, s), 1.9˜2.2 (2H, m),                                           2.2 (2H, q), 4.2 (2H, t), 5.0˜5.2                                        (1H, m)                                      23 1 CH.sub.3 CH.sub.2 CH.sub.2 CO                                                          C.sub.14 H.sub.26 O.sub.2 Oil                                                         ##STR49##                                                                           ##STR50##                                                                          226  0.9˜1.1 (5H, m), 0.99 (3H, d),                                           1.2˜1.5 (5H, m), 1.6 (3H, s),                                            1.72 (3H, s), 1.9˜ 2.2 (2H, m),                                          2.2 (2H, t), 4.2 (2H, t), 5.0˜5.2                                        (1H, m)                                      24 2 CH.sub.3 CO                                                                             C.sub.17 H.sub.30 O.sub.2 Oil                                                        ##STR51##                                                                           ##STR52##                                                                          266  0.99 (3H, d), 1.2˜1.5 (5H, m),                                           1.6 (6H, s), 1.72 (3H, s),                                                     1.9˜2.2 (6H, m), 2.0 (3H, s), 4.2                                        (2H, t), 5.0˜ 5.2 (2H, m)              25 2 CH.sub.3 CH.sub.2 CO                                                                   C.sub.18 H.sub.32 O.sub.2 Oil                                                         ##STR53##                                                                           ##STR54##                                                                          280  0.99 (3H, d), 1.1 (3H,                                                         t), 1.2˜1.5 (5H, m), 1.6 (6H, s),                                        1.72 (3H, s), 1.9˜2.2 (6H, m),                                           2.2 (2H, q), 4.2 (2H, t), 5.0˜5.2                                        (2H, m)                                      26 2 CH.sub.3 CH.sub.2 CH.sub.2 CO                                                          C.sub.19 H.sub.34 O.sub.2 Oil                                                         ##STR55##                                                                           ##STR56##                                                                          294  0.9˜1.1 (5H, m), 0.99 (3H, d),                                           1.2˜1.5 (5H, m), 1.6 (6H, s),                                            1.72 (3H, s), 1.9˜ 2.2 (6H, m),                                          2.2 (2H, t), 4.2 (2H, t), 5.0˜5.2                                        (2H, m)                                      27 3 CH.sub.3 CH.sub.2 CO                                                                   C.sub.23 H.sub.40 O.sub.2 Oil                                                         ##STR57##                                                                           ##STR58##                                                                          348  0.99 (3H, d), 1.1 (3H,                                                         t), 1.2˜1.5 (5H, m), 1.6 (9H, s),                                        1.72 (3H, s), 1.9˜2.2 (10H, m),                                          2.2 (2H, q), 4.2 (2H, t), 5.0˜5.2                                        (3H, m)                                      28 3 CH.sub.3 CH.sub.2 CH.sub.2 CO                                                          C.sub.24 H.sub.42 O.sub.2 Oil                                                         ##STR59##                                                                           ##STR60##                                                                          362  0.9˜1.1 (5H, m), 0.99 (3H, d),                                           1.2˜1.5 (5H, m), 1.6 (9H, s),                                            1.72 (3H, s), 1.9˜ 2.2 (10H, m),                                         2.2 (2H, t), 4.2 (2H, t), 5.0˜5.2                                        (3H, m)                                      29 4 H       C.sub.25 H.sub.44 O Oil                                                               ##STR61##                                                                           ##STR62##                                                                          360  0.99 (3H, d), 1.2˜1.5 (5H, m),                                           1.6 (12H, s), 1.72 (3H, s),                                                    1.9˜2.2 (15H, m), 3.6 (2H, t),                                           5.0˜5.2 (4H, m)                        30 4 CH.sub.3 CO                                                                            C.sub.27 H.sub.46 O.sub.2 Oil                                                         ##STR63##                                                                           ##STR64##                                                                          402  0.99 (3H, d), 1.2˜1.5 (5H, m),                                           1.6 (12H, s), 1.72 (3H, s),                                                    1.9˜2.2 (14H, m), 2.0 (3H, s),                                           4.2 (2H, t), 5.0˜ 5.2 (4H, m)          31 4 CH.sub.3 CH.sub.2 CO                                                                   C.sub.28 H.sub.48 O.sub.2 Oil                                                         ##STR65##                                                                           ##STR66##                                                                          416  0.99 (3H, d), 1.1 (3H,                                                         t), 1.2˜1.5 (5H, m), 1.6 (12H,                                           s), 1.72 (3H, s), 1.9˜2.2 (15H,                                          m), 2.2 (2H, q), 4.2 (2H, t),                                                  5.0˜5.2 (4H, m)                        32 4 CH.sub.3 CH.sub.2 CH.sub.2 CO                                                          C.sub.29 H.sub.50 O.sub. 2                                                            ##STR67##                                                                           ##STR68##                                                                          430  0.9˜1.1 (5H, m), 0.99 (3H, d),                                           1.2˜1.5 (5H, m), 1.6 (12H, s),                                           1.72 (3H, s), 1.9˜2.2 (14H, m),                                          2.2 (2H, t), 4.2 (2H, t), 5.0˜5.2                                        4H, m)                                       __________________________________________________________________________

EXAMPLE 33

    ______________________________________                                         Preparation of tablets                                                         ______________________________________                                         Product obtained in Example 1                                                                       50 g.                                                     Silicic anhydride    30 g.                                                     Crystalline cellulose                                                                               50 g.                                                     Corn starch          36 g.                                                     Hydroxypropylcellulose                                                                              10 g.                                                     Calcium stearate      4 g.                                                     ______________________________________                                    

This composition was processed in the conventional manner to obtain tablets (180 mg. per one tablet).

EXAMPLE 34

    ______________________________________                                         Preparation of hard gelatin capsules                                           ______________________________________                                         Product obtained in Example 2                                                                         50 g.                                                   Silicic anhydride      35 g.                                                   Silicic anhydride, hydrated                                                                            5 g.                                                   Crystalline cellulcse  50 g.                                                   Hydroxypropylcellulose  6 g.                                                   Corn starch            49 g.                                                   Talc                    5 g.                                                   ______________________________________                                    

This composition was granulated in the conventional manner and charged into gelatin hard capsules (No. 3); 200 mg. per one capsule.

EXAMPLE 35

    ______________________________________                                         Preparation of tablets                                                         ______________________________________                                         Product obtained or Example 17                                                                      50 g.                                                     Silicic anhydride    30 g.                                                     Crystalline cellulose                                                                               50 g.                                                     Corn starch          36 g.                                                     Hydroxypropylcellulose                                                                              10 g.                                                     Calcium stearate      4 g.                                                     ______________________________________                                    

This composition was processes in the conventional manner to obtain tablets (180 mg. per one tablet).

EXAMPLE 36

    ______________________________________                                         Preparation of hard gelatin capsules                                           ______________________________________                                         Product obtained in Example 18                                                                        50 g.                                                   Silicic anhydride      35 g.                                                   Silicic anhydride, hydrated                                                                            5 g.                                                   Crystalline cellulose  50 g.                                                   Hydroxypropylcellulose  6 g.                                                   Corn starch            49 g.                                                   Talc                    5 g.                                                   ______________________________________                                    

This composition was granulated in the conventional manner and charged into gelatin hard capsules (No. 3); 200 mg. per one capsule. 

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
 1. A compound having the formula: ##STR69## wherein X is --COOR₁ or --CH₂ OR₂, in which R₁ is hydrogen or alkyl having one to four carbon atoms and R₂ is hydrogen or aliphatic acyl having one to four carbon atoms; and n is an integer of one to four.
 2. A compound as claimed in claim 1, in which X is --COOR₁.
 3. A compound as claimed in claim 1, in which X is --CH₂ OR₂.
 4. A compound as claimed in claim 1 which is (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid.
 5. A compound as claimed in claim 1 which is ethyl (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate.
 6. A compound as claimed in claim 1 which is (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrien-1-ol.
 7. A compound as claimed in claim 1 which is (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienyl acetate.
 8. A pharmacological composition for the treatment of liver hepatitis comprising a therapeutically effective amount of a compound having the formula: ##STR70## wherein X is --COOR₁ or --CH₂ OR₂, in which R₁ is hydrogen or a lower alkyl group and R₂ is hydrogen or aliphatic acyl having one to four carbon atoms; and n is an integer of one to four, in combination with a pharmacological carrier.
 9. A composition as claimed in claim 8, in which X is --COOR₁.
 10. A composition as claimed in claim 8, in which X is --CH₂ OR₂.
 11. A composition as claimed in claim 8 which said compound is (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid.
 12. A composition as claimed in claim 8 which said compound is ethyl (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate.
 13. A composition as claimed in claim 8 which said compound is (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrien-1-ol.
 14. A composition as claimed in claim 8 which said compound is (E, E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienyl acetate. 